Background The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis. Methods International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1–infected antiretroviral therapy–naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. Results For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65–86%) for DTG and 82% (36/44, 95% CI 70–93%) for EFV. The DTG nonresponses were driven by non–treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS. Conclusions Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated. Clinical Trials Registration NCT02178592.

OBJECTIVECognitive impairment (CI) and major depressive disorder (MDD) remain prevalent in treated HIV-1 disease; however, the pathogenesis remains elusive. A possible contributing mechanism is immune-mediated degradation of tryptophan (TRP) via the kynurenine (KYN) pathway, resulting in decreased production of serotonin and accumulation of TRP degradation products. We explored the association of these biochemical pathways and their relationship with CI and MDD in HIV-positive (HIV+) individuals.METHODSIn a cross-sectional analysis, concentrations of neopterin (NEO), tumor necrosis factor-alpha, TRP, KYN, KYN/TRP ratio, phenylalanine (PHE), tyrosine (TYR), PHE/TYR ratio, and nitrite were assessed in the cerebrospinal fluid (CSF) and plasma of HIV+ (n = 91) and HIV-negative (HIV−) individuals (n = 66). CI and MDD were assessed via a comprehensive neuropsychological test battery. A Global Deficit Score ≥0.5 was defined as CI. Nonparametric statistical analyses included Kruskal–Wallis and Mann–Whitney U tests, and multivariate logistic regression.RESULTSFollowing Bonferroni correction, NEO concentrations were found to be greater in CSF and TRP concentration was found to be lower in the plasma of HIV+ versus HIV− individuals, including a subgroup of aviremic (defined as HIV-1 RNA <50 cps/mL) HIV+ participants receiving antiretroviral therapy (n = 44). There was a nonsignificant trend toward higher KYN/TRP ratios in plasma in the HIV+ group (P = 0.027; Bonferroni corrected α = 0.0027). In a logistic regression model, lower KYN/TRP ratios in plasma were associated with CI and MDD in the overall HIV+ group (P = 0.038 and P = 0.063, respectively) and the aviremic subgroup (P = 0.066 and P = 0.027, respectively), though this observation was not statistically significant following Bonferroni correction (Bonferroni corrected α = 0.0031).CONCLUSIONSWe observed a trend toward lower KYN/TRP ratios in aviremic HIV+ patients with CI and MDD.

The mechanisms underlying central nervous system (CNS) toxicities in antiretroviral-treated persons living with HIV (PLWH) remain elusive. We investigated the associations between markers of tryptophan metabolism and measurements of CNS toxicity in PLWH. In a prospective study, virologically suppressed PLWH receiving efavirenz-containing antiretroviral regimens with ongoing CNS toxicity were switched to dolutegravir-containing regimens and followed up for 12 weeks. Plasma tryptophan and kynurenine concentrations and the kynurenine/tryptophan ratio were calculated. Ten CNS toxicities were graded according to the ACTG adverse events scale. Scores ranged from 0 (none) to 3 (severe) and were summed, giving a total from 0 to 30. Paired-samples t tests and linear mixed model analyses were conducted to assess changes in, and relationships between, laboratory and clinical parameters. Mean kynurenine plasma concentration increased from baseline to week 12 (2.15 to 2.50 μmol/L, p = 0.041). No significant changes were observed for tryptophan (54.74 to 56.42 μmol/L, p = 1.000) or kynurenine/tryptophan ratio (40.37 to 41.08 μmol/L, p = 0.276). Mean CNS toxicity score decreased from 10.00 to 4.63 (p < 0.001). Plasma kynurenine concentration correlated with CNS toxicity score: for every 1 μmol/L increase in kynurenine concentration observed, a 1.7 point decrease was observed in CNS toxicity score (p < 0.038). A similar trend was observed for the kynurenine/tryptophan ratio: for every 1 μmol/mmol increase observed in kynurenine/tryptophan ratio, a 0.1 point decrease was observed in CNS toxicity score (p = 0.054). Switching from efavirenz to dolutegravir was associated with increases in plasma kynurenine concentration and improvements in CNS toxicity scores. Underlying mechanisms explaining the rise in kynurenine concentrations need to be established.